The mechanisms involved in the development of irreversible pulmonary vascular pathology associated with pulmonary hypertension in the young have not been elucidated. A recent hypothesis was that the pathologic and hemodynamic alterations are regulated by endothelial cell derived relaxing factor (EDRF) and that changes in EDRF production may be a major contributor. This hypothesis was tested in dogs and weanling swine who had 6-8 mm polytetrafluorethylene conduits anastamosed to the left pulmonary artery and aorta. At a second operation, flows were diverted such that the right lung was hyperperfused and normotensive and the left lower lobe was made hypertensive and hyperperfused. Three to six months later isolated lobar perfusion was used to provide a wide variety of flow-pressure conditions. EDRF stimulants; bradykinin, acetylcholine a calcium ionophore and adenosine triphosphate were tested as vasodilators after preconstuction with prostaglandin PGFa and inhibition of cyclooxygenase metabolism with indomethacin. The results demonstrated no diminution in vascular response to EDRF stimulants in normal and hyperperfused lungs. A lipoxygenase inhibitor was shown to completely inhibit vasodilatory responses to bradykinin but the responses were not inhibited by an enzymatic cyclooxygenase inhibitor. Species differences were also identified. These data suggest that endothelial derived relaxant factor can play a major role in the development of irreversible pulmonary hypertension and that the pathway of expression is probably through lipoxygenase derived metabolites of arachodinic acid.